title: Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity.
abstract: BACKGROUND
  Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor.
  
  
  RESULTS
  Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM). Applying a whole blood assay, IC(50) values of pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-8, IL-1beta) were found to be positively correlated with the K(i)-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1.
  
  
  CONCLUSIONS
  The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account for curcumin's potency as an anti-inflammatory and anti-tumor agent. The findings support the use of curcumin as a potential therapeutic agent.
authors.affiliation: Institute of Biochemistry, University of Leipzig, Leipzig, Germany.
authors.forename: Thore
authors.initials: T
authors.lastname: Santel
authors.forename: Gabi
authors.initials: G
authors.lastname: Pflug
authors.forename: Nasr Y A
authors.initials: NY
authors.lastname: Hemdan
authors.forename: Angelika
authors.initials: A
authors.lastname: Schäfer
authors.forename: Marcus
authors.initials: M
authors.lastname: Hollenbach
authors.forename: Martin
authors.initials: M
authors.lastname: Buchold
authors.forename: Anja
authors.initials: A
authors.lastname: Hintersdorf
authors.forename: Inge
authors.initials: I
authors.lastname: Lindner
authors.forename: Andreas
authors.initials: A
authors.lastname: Otto
authors.forename: Marina
authors.initials: M
authors.lastname: Bigl
authors.forename: Ilka
authors.initials: I
authors.lastname: Oerlecke
authors.forename: Antje
authors.initials: A
authors.lastname: Hutschenreuther
authors.forename: Antje
authors.initials: A
authors.lastname: Hutschenreuter
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sack
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.forename: Claudia
authors.initials: C
authors.lastname: Birkemeyer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schellenberger
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.forename: Mathias
authors.initials: M
authors.lastname: Platzer
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiss
authors.forename: Mookambeswaran A
authors.initials: MA
authors.lastname: Vijayalakshmi
authors.forename: Monika
authors.initials: M
authors.lastname: Krüger
authors.forename: Gerd
authors.initials: G
authors.lastname: Birkenmeier
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D013379:Substrate Specificity
chemical_list: D000893:Anti-Inflammatory Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005419:Flavonoids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010636:Phenols; D059808:Polyphenols; D007770:L-Lactate Dehydrogenase; D007791:Lactoylglutathione Lyase; D003474:Curcumin